Hematopoietic stem cells (HSCs) have the capacity to generate all the cells of the blood. A defining feature of HSCs is their ability to perpetuate themselves through self-renewal. While the phenotypic and functional properties of HSCs have been extensively characterized a fundamental question that remains unanswered is how self-renewal is regulated. Our work has revealed that I_-catenin,a key mediator of Wnt signaling, can promote self-renewal of HSC in vitro. Moreover, Axin, which enhances _-catenin degradation, causes inhibition of growth and reconstitution by HSC. These studies reveal an important role for 13-cateninin the regulation of HSC growth and self-renewal. To further elucidate the role of Wnt and {3-cateninsignaling in HSC, we propose to 1) Determine whether Wnt signaling regulates HSC function in vivo, 2) Examine whether the effects of I_-catenin and Axin on HSC reflect the activity of Wnt proteins and 3) Identify the molecular mechanisms by which I_-catenin exerts its effects on HSC self-renewal. These studies will not only advance our understanding of self-renewal, a key characteristic of all stem cells, but will also help develop strategies for in vitro expansion of stem cells, and thereby contribute to improving transplantation therapies for hematopoietic and degenerative disorders.